This invention relates to novel amino- and alkylamino-substituted spirohydantoins and derivatives thereof useful as inhibitors as the enzyme aldose reductase and in the treatment of certain chronic complications arising from diabetes mellitus, such as diabetic cataracts, neuropathy and retinopathy.
In the past various attempts have been made to obtain new antidiabetic agents. Generally these efforts have involved synthesis of new organic compounds, particularly sulfonyl ureas, and determination of their ability to substantially lower blood sugar levels when administered orally. However, little is known about the effect of organic compounds in preventing or alleviating chronic complications of diabetes, such as diabetic cataracts, neuropathy and retinopathy. U.S. Pat. No. 3,821,383 discloses aldose reductase inhibitors like 1,3-dioxo-1H-benz[d,e]-isoquinoline-2(3H)-acetic acid and derivatives thereof to be useful for the treatment of these conditions. More recently, U.S. Pat. Nos. 4,117,230 and 4,130,714 disclose a series of spirohydantoins useful as aldose reductase inhibitors. Such aldose reductase inhibitors function by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses, such as glucose and galactose to the corresponding polyols, such as sorbitol and galacticol, in humans and other animals. In this way, unwanted accumulations of galacticol in the lens of galactosemic subjects and of sorbitol in the lens, peripheral nervous tissue and kidney of diabetic subjects are prevented or reduced. Accordingly, such compounds are of therapeutic value as aldose reductase inhibitors for controlling certain chronic diabetic complications, especially those of an occular nature, since it is known in the art that the presence of polyols in the lens of the eye leads to cataract formation with a concomittant loss of lens clarity.